No treatment on the market has been proved to slow human aging--the buildup of molecular and cellular damage that increases vulnerability to infirmity as we grow older. But one intervention, consumption of a low-calorie yet nutritionally balanced diet, works incredibly well in a broad range of animals, increasing longevity and prolonging good health. Those findings suggest that calorie restriction could delay aging in humans, too.

Unfortunately, for maximum benefit, people would probably have to reduce their calorie intake by roughly 30 percent, equivalent to dropping from 2,500 calories a day to 1,750. Although a few hardy souls are currently attempting to do this, most mortals could not stick to that harsh a regimen, especially for years on end. But what if someone could create a pill that mimicked the physiological effects of eating less without actually forcing people to go hungry? Could such a calorie-restriction mimetic, as we call it, enable people to stay healthy longer, postponing age-related disorders (such as diabetes, atherosclerosis, heart disease and cancer) until very late in life?

We first posed this question in the mid-1990s, after we came upon a chemical agent that, in rodents, seemed to reproduce many of calorie restriction's benefits. Since then, we and others have been searching for a compound that would safely achieve the same feat in people. We have not succeeded yet, but our failures have been informative and have fanned hope that calorie-restriction, or CR, mimetics can indeed be developed eventually.

Our hunt for CR mimetics grew out of our desire to better understand calorie restriction's many effects on the body. Scientists first recognized the value of the practice more than 60 years ago, when they found that rats fed a low-calorie diet lived longer on average than free-feeding rats and had a reduced incidence of conditions that become increasingly common in old age. What is more, some of the treated animals survived longer than the oldest-living animals in the control group, which means that the maximum life span (the oldest attainable age), not merely the average life span, increased.

The rat findings have been replicated many times and extended to creatures ranging from yeast to fruit flies, worms, fish, spiders, mice and hamsters. Until fairly recently, the studies were limited to short-lived creatures genetically distant from humans. But a long-term study in dogs was published a couple of years ago to show that CR could be effective for our pets as well. A few long-term projects under way in a species more closely related to humans--the rhesus monkey--suggest that primates respond to calorie restriction almost identically to rodents, which makes us more optimistic than ever that CR mimetics could help people.

The monkey projects--initiated by our group at the National Institute on Aging in the late 1980s and by our colleagues at the University of WisconsinMadison in the early 1990s--demonstrate that, compared with control animals that eat normally, calorie-restricted monkeys have lower body temperatures and levels of the pancreatic hormone insulin, and as young adults they retain more youthful levels of certain hormones (such as DHEAS, or dehydroepiandrosterone sulfate) that tend to fall with age.

The animals also look better on indicators of risk for age-related diseases. For example, they have lower blood pressure and triglyceride levels (signifying a decreased likelihood of heart disease), and they have more normal blood glucose levels (pointing to a reduced risk for diabetes, which is marked by unusually high blood glucose levels). They and the other monkeys must be followed still longer, however, before we will know whether low food intake can increase both average and maximum life spans in monkeys: rhesus monkeys typically live about 25 years and sometimes up to 40. Findings in primates bode well for the possibility that CR will have beneficial effects in humans. Indeed, we have demonstrated that biological hallmarks of CR, such as decreased insulin and body temperature and a slowed rate of decline in serum DHEAS levels, are associated with better survival in men from the Baltimore Longitudinal Study of Aging.